Although it is well accepted that early cancer screening would increase survival dramatically, no test currently exists for accurate and cost-effective screening of major cancers. A notable exception is cervical cancer, which has been relegated from the 1st to the 14th cause of cancer deaths in women due to the introduction of the Pap- smear as an initial screening test that is followed by a more invasive colposcopy. However, no such two-tier screening paradigm is available for other cancers. Recently our group at Northwestern University, in collaboration with Northshore University Health System, developed a new cancer screening paradigm in which the presence of a cancerous tumor is detected by a simple swab of histologically normal cells from surrogate sites via Partial Wave Spectroscopic (PWS) microscopy identification of field carcinogenesis. Field carcinogenesis posits that the genetic/environmental milieu that leads to a focal tumor exists not only at that particular location, but affects the entire organ. Our data from more than 750 patients showed that the PWS analysis of the cells obtained from a swab from these surrogate sites (e.g., buccal cells lung cancer, rectal cells colon cancer, etc.) could discriminate between non-cancerous and cancer patients. While these data support the idea that PWS is sensitive to field carcinogenesis, it lacks specificity to those macromolecules/organelles that play a critical role i cancer development/progression (e.g., chromatin complexes). Our recent data demonstrated that histological dyes can provide molecular specificity to PWS by the targeted amplification of scattering from specific organelles or macromolecular structures. Hence, in this proposal we will first develop a new high-throughput molecular PWS (HT-mPWS) instrument that will be both molecular-specific and nanoscale-sensitive to the intracellular organelle. We will next identify the organelles/macromolecules that undergo the greatest change in the nanoscale during field carcinogenesis. Since there will be many dyes that can target a specific organelle, we will identify an optimal dye that will give >10 fold enhancement of scattering from a targeted organelle. Although HT-mPWS is a platform technology to screen for different types of cancers, our initial test case will be focused on lung cancer screening. Lung cancer is the leading cause of cancer deaths among Americans, with smoking being the most important risk factor accounting for ~90% of cancers. Our approach to lung cancer screening will be to identify the presence or absence of a lung tumor by a simple swab of histologically normal buccal cells. Hence, we will select optimal dyes that will maximize the sensitivity of buccal cells to lung cancer. We will next test the HT-mPWS system, the optimal dyes and the corresponding molecular markers on a training set of 100 patients and a prediction rule to diagnose lung cancer patients will be subsequently developed. Finally, we will test the prediction rule on an independent blinded study of 200 patients. The successful completion of this proposal will lead to a multi- center clinical trial and subsequently to clinical implementation of HT-mPWS for screening major cancers.